Mixture of carboxylic acids for treating patients with kidney failure

ABSTRACT

A mixture of carboxylic acids: citric acid, succinic acid, fumaric acid and malic acid, and any possible combinations thereof. This product is used orally or also intravenously, in the treatment of patients with chronic renal failure, hyperammonemia or human conditions having negative nitrogen balance. This product is beneficial in decreasing the serum values of urea and serum ammonium, while promoting by transamination of the oxalacetate formed via succinate, fumarate and malate, the biosynthesis of non-essential amino acids; by transamination of the alpha ketoglutarate formed via citrate, it generates glutamic acid and related amino acids such as glutamine. This treatment prevents, preserves and even improves kidney function. In other patients it delays deterioration of renal function and the urgent need for renal replacement therapy. In others, it is used as a supplemental renal replacement treatment to improve the patient&#39;s quality of life and improve laboratory parameters.

II.1. Chronic renal failureII.2. Acute renal failureII.3. Chronic or acute hepatopathy occurring with hyperammonemiaII.4. Congenital diseases with enzymatic alterations of the urea cycleII.5. Pathological human conditions having negative nitrogen balance,namely:

II.5.1. Sepsis II.5.2. Burns II.5.3. Postoperative

II.5.4. Complement of parenteral nutrition entailing mixture of aminoacidsII.5.5. Enteral nutrition supplement

II.5.6. Sarcopenia II.5.7. Cancer II.5.8. Malnutrition II.6. DiabetesMellitus

With regard to Chronic Kidney Disease (CKD), there has been a dramaticincrease in both the prevalence and incidence of this disease inpractically the whole world. The last stage of this group of chronickidney diseases is the End-Stage Renal Disease (ESRD). Figures such asthe following show the panorama: a recent study in Mexico in 2010entitled Epidemiology of Chronic Renal Failure in Mexico estimated anincidence of 377 new cases per million inhabitants and a prevalence of1142 cases per million inhabitants, as well as about 52,000 patients inrenal replacement therapy to that date. In the United States of America,according to the 2010 and 2011 Annual Data Report, one out of tenAmerican adults has some degree of CKD. The incidence of CKD increasessubstantially in people over 65 years or older. The incidence in thisage group doubled from 2000 to 2008. As for the incidence of ESRD inthat country, it was estimated at a little more than 360 new cases permillion inhabitants; with regard to the prevalence at the end of 2009,871,000 patients received renal replacement therapy. Between 1980 and2009, the prevalence of ESRD increased by 600% with a prevalence of1,738 patients per million inhabitants. Regarding CKD stages one tofive, it is estimated that in Mexico 8.5% of the Mexican population hassome degree of CKD, defined as a reduction of the glomerular filtrationrate lower than 60 ml/min/1.73 m² of body surface. Meanwhile, a reportby Sarah L. White et al. from the World Health Organization reports thatmore than 1.4 million people in the world are in some type of renalreplacement therapy, 80% of which is provided in developed countries.

Currently, the most frequent causes of ESRD are: Non-insulin dependentdiabetes mellitus as the first cause, Systemic Arterial Hypertension asthe second, and miscellaneous glomerulopathies as the third cause. Thefirst two pathologies (DM II and SAH), combined with a longer lifeexpectancy of the world population, augur an unfavorable panoramaregarding the CKD and its final stage, the ESRD, so the current figuresshow an upward trend.

This ESRD is accompanied by: 1) extremely high treatment costs, 2) highmorbidity, 3) increased mortality, and 4) greatly reduced quality oflife.

With regard to item (1), extremely high treatment costs, ESRD isconsidered a catastrophic disease, since it can mean ruin for mostfamilies and a significant economic burden for national health systems.In the United States of America, according to the 2009 Annual ReportData System, the cost for a hemodialysis patient was $80,000 dollarsannually, $60,000 dollars for peritoneal dialysis patients and $30,000dollars per year for renal transplant patients. In other countries withavailable information, the annual costs per patient are: $7,332 USD inBrazil, $7,500 USD in China, $5,000 USD in India and $6,240 USD inIndonesia (White, Chadban, Jan, Chapman, & Cass, 2008). In Mexico, thecosts of hemodialysis and continuous ambulatory peritoneal dialysis wereestimated at $21,861 USD and $8,489 USD respectively (Schettino Maimone,et al., 1997).

In order to stop the alarming growth of the ESRD “epidemic” and,consequently, reduce the costs of its treatment, the current trendworldwide is towards prevention of CKD; however, considering that thepathologies leading to CKD and finally to its last stage, ESRD, are DMII and SAH, and since these two pathologies are becoming more frequentin the general population, the picture for the future is gloomy. Such isthe situation that widely recognized international organizations such asthe National Kidney Foundation (NKF), the International Society ofNephrology (ISN) and the World Health Organization (WHO) endorsed thelaunching of the first World Kidney Day in March 2006.

Regarding morbidity, despite medical and technical advances, patientswith end-stage renal disease treated with dialysis often continue tohave problems. Constitutional symptoms such as fatigue and weaknesspersist even with adequate correction of anemia with erythropoietin.Progressive cardiovascular disease, autonomic and peripheral neuropathy,bone disease and sexual dysfunction are common even in patients who maybe adequately treated with dialysis, which is not surprising since eventhe most efficient dialysis regimens contribute only 10 to 20% of theremoval of low molecular weight solutes such as urea. Removal of solutesof higher molecular weight is still less efficient than in normalconditions two kidneys with 1 million nephrons each functioning at 100%would perform. In addition, dialysis patients may become dependent ontheir families or caregivers in terms of physical, emotional andfinancial assistance.

In regard to mortality, the United States Renal Data System (USRDS)shows the following figures in its 2009 report according to statisticsfrom the United States of America:

1.—The average life expectancy of the American citizen over 55 years ofage is 26 years, that is 81 years.2.—The average life expectancy of the American citizen over 55 years ofage who receives a kidney transplant from a living individual is 15years, that is 70 years; but,3.—The average life expectancy of a patient over 55 years of age ondialysis treatment is only 5 years, i.e., 60 years.4.—The overall life expectancy of all patients in the United States whoundergo dialysis treatment is 3 years. This information, in theshortened global life expectancy, is a consequence of the fact that inpatients who start dialysis treatment the average life at the beginningof the dialysis treatment is greater than 65 years. These results ofhemodialysis treatment (because in the United States 90% of patientsreceive hemodialysis versus peritoneal dialysis in only about 10%) havenot changed substantially over the past 20 years.

In Mexico, according to the study dated February 2010, the averagesurvival for the two modalities of peritoneal dialysis was 30.6 monthsand 32 months for patients on hemodialysis.

III. STATE OF THE ART

Until now, the treatment of patients with Stage V chronic kidneydisease, also known as End-Stage Renal Disease, defined as a glomerularfiltration rate of less than 15 milliliters/minute/1.73 m² of bodysurface area, has consisted of:

1. Substitute or Replacement Renal Treatment, which consists of threeoptions with modalities, in turn, in each one of them:1.a. Hemodialysis is a treatment entailing high costs reported in theUnited States of about $80,000 USD annually. In Mexico an overall lifeexpectancy of 32 months is estimated according to the study“Epidemiology of Chronic Renal Disease in Mexico.” On the other hand, inthe United States of America an average global life expectancy of around36 months is reported. With regard to quality of life, it is necessaryto mention that patients, in most cases, except for those in whichhemodialysis is performed at home, should go to a specialized hospitalor clinic three times a week, remaining 3 to 4 hours in the dialysissession.1.b. Peritoneal Dialysis, with a reported cost in the United States ofAmerica of about $60,000 per year and a similar life-time tohemodialysis in that country. In Mexico there was an overall averagelife expectancy of 30.6 months (Méndez-Durán, Méndez-Bueno, Tapia-Yáñez,Muñoz Montes, & Aguilar-Sánchez, 2010). It is necessary to mention thatits main complication is the generally bacterial peritonitis with anincidence rate of one event per patient per year and, if severe, arecovery time of 28 days (Ministry of Health, 2009).1.c. Kidney transplantation with two modalities, namely, cadaveric donorwith a survival similar to that of patients in the peritoneal dialysisor hemodialysis programs, or living donor with an average lifeexpectancy of 15 to 17 years; as well as a great improvement in thequality of life and an important decrease in the annual costs oftreatment that in the United States of America were estimated at around30,000 dollars per year.

In addition to renal replacement therapy, either with a) hemodialysis,b) peritoneal dialysis, or c) renal transplantation, in a complementary,adjuvant, adjunctive manner, but not supplementary, or as replacement ofsaid renal replacement therapies, adjuvant treatments are provided,consisting of:

2. Phosphorus chelating treatments—since patients with ESRD havehyperphosphatemia—it is necessary to add phosphorus chelating drugs topatients with hyperphosphatemia immediately after meals to chelate andfix phosphorus in food. These drugs include: 1) aluminum hydroxide,currently in disuse because of its proven toxicity, resulting inencephalopathy and osteomalacia. Another therapy consists of calciumsalts, 2) calcium acetate or 3) calcium carbonate, which also chelatephosphorus; another, 4) lanthanum carbonate and recently a phosphoruschelator consisting of a copolymer known as 5) sevelamer.3. Adjuvant treatment for anemia of renal failure, which in mostpatients is secondary to a deficiency of renal production oferythropoietin. Treatment with recombinant erythropoietins manufacturedby biotechnology, such as 1) erythropoietin alfa, 2) erythropoietinbeta, and 3) erythropoietins with a higher degree of glycosylation andlonger shelf life such as epoetin, 4) darbepoetin and 5) CERA.4. Treatment with calcitriol, the active form of vitamin D, since theinsufficient kidney has a marked decrease in the conversion of inactivevitamin D to the activated form 1, 25 dihydroxy cholecalciferol, whichis involved in the intestinal absorption of calcium.5. Prevention and treatment of hyperkalemia mainly by: 1) avoidingconsumption of foods rich in potassium and 2) avoiding and correctingmetabolic acidosis, a condition that aggravates hyperkalemia, andultimately, when hyperkalemia is severe, medicines are used to lowerserum potassium such as: 3) polarizing solutions consisting of glucosesolutions and insulin that divert extracellular potassium to theintracellular compartment, 4) beta-adrenergic drugs such as salbutamol,5) loop diuretics such as furosemide that removes potassium via thekidney, and 6) sodium potassium exchange resins such as kayexalate(sodium polystyrene sulfonate) that decrease the intestinal absorptionof potassium.6. Treatment and prevention of hypo calcemia with supplements of calciumsalts such as: 1) calcium acetate, 2) calcium carbonate, 3) calciumgluconate, 4) coral calcium and/or 5) oseinic calcium.7. Treatment of fluid overload, if any, with fluid restriction and useof diuretics, especially loop.8. Treatment of hyperuricemia, if any, with allopurinol.9. Treatment of co-morbid conditions such as treatment of diabetesmellitus, treatment of hypertension, treatment of glomerulopathies ordiseases that caused chronic kidney disease, treatment of pre-existingcardiovascular disease, treatment of malnutrition, if any, which is verycommon, and other conditions such as hypercholesterolemia and/orhypertriglyceridemia.10. Treatment with sulodexide in patients with diabetic nephropathy.European patent EP-0624374-B1, entitled “Use of Sulodexide andMedicaments Containing It for the Treatment of Diabetic Nephropathy,” acomplication that may result in ESRD, proposes the use of such amolecule, belonging to the group of glucosaminoglycans of natural originand extracted from the intestinal mucosa of mammals, in the therapeuticarsenal to treat CKD and its final stage, ESRD. This patent states thatsulodexide “causes a significant and significant decrease in urinaryalbumin excretion.”11. Treatment with sulphated polysaccharides combined with L-aminoacids, as described in the Chinese patent CN-1285340-C, which exerts animprovement in renal function indexes and serum albumin levels.12. Supplementary and adjuvant food treatment consisting of mixtures ofketo analogs of essential branched chain amino acids such as valineketo-analogue, leucine keto-analogue, isoleucine keto-analogue andmethionine hydroxyalkane. These in combination with different essentialL-amino acids constitute a suggested treatment for patients in stage 5and 4 renal disease. In the pre-dialytic stage, corresponding to stages4 and 3 of chronic kidney disease with glomerular filtration rates of 15to 29 and 30 to 59 ml./min/1.73 m² of body surface respectively, anadjusted hypo protein diet of 0.6 to 0.8 grams of protein per kilo ofweight per day is prescribed, preferably proteins of high biologicalquality because of their higher content of essential amino acids(tryptophan, histidine, arginine, lysine, methionine, valine, leucine,isoleucine, phenylalanine, threonine) primarily whey protein and eggwhite protein. The above in order to reduce as much as possible agreater intake than the necessary proteins which, ingested in excess or,very important, in poor biological quality because of its low content ofessential amino acids, would be subject to catabolic metabolism, which,as a consequence of the deamination of 19 alpha-L-amino acids, wouldgenerate high amounts of ammonium, which in subsequent metabolic steps,specifically through the urease cycle or Krebs-Henseleit, mainlyperformed in the liver at the level of the hepatocyte cytosol, generatesurea as the end product of this cycle. Urea, also known as carbamide,subsequently returns to the general circulation and is eliminated fromour body mainly via the kidney. A small fraction, up to 10% of urea, isremoved with sweat, and about a quarter of the circulating urea in bloodpasses into the intestine where, by action of the urease of ureolyticbacteria residing in the intestine, it is converted again to ammoniumand carbon dioxide, said ammonium being absorbed to the portalcirculation and its passage to the liver.

It is in this modality of coadjuvant and complementary dietary treatmentof chronic renal disease (point number 12 of our presentation) in whichpatients who develop end-stage renal disease receive a treatmentconsisting of renal replacement therapy: peritoneal dialysis,hemodialysis or renal transplantation. In addition, they are given atreatment for co-morbid conditions and alterations characteristic ofchronic renal failure. In addition to the aforementioned measures andtreatments, a hypo-protein and hypercaloric diet is prescribed, whichtypically ranges from 0.6 to 0.8 grams of protein per kilo of weight perday, in order to avoid an excess of protein intake which wouldconsequently cause an excessive intake of the amino acids that are partof it. Finally this excess of amino acids would lead to a catabolismthereof, since human beings, unlike the handling of carbohydrates, fattyacids and glycerol contained in nutrients, do not have polymericmacromolecules for storage, as is the case of glucose that byglycogenesis is stored as glycogen in liver and muscle; or oils and fatsfrom food stored in the form of triacylglycerols in the adipocytes offat tissue—which is not the case of amino acids. Amino acids that arenot used in anabolism, after amino group deamination, their carbonskeletons enter catabolic pathways to generate energy. Then, the aminogroup (NH2) generates ammonia (NH3) formation that immediately in theaqueous medium of the organism is converted to ammonium (NH4), which inthe next metabolic step enters the urea cycle, where it becomes urea tobe eliminated through the kidney mainly.

In order to be able to influence and intervene at this stage, i.e., toavoid excessive or unnecessary and undesirable ammonium formation, themedical community has long sought, designed and used treatmentmodalities that, on the one hand, reduce protein intake, but at the sametime maintain a positive nitrogen balance and an energy balance to avoidthe excessive formation of nitrogenous waste products. In this regard,the U.S. Pat. No. 2,457,820-A proposed a mixture of essential aminoacids administered parenterally, rectally or orally to maintain anappropriate nitrogen balance in those medical conditions where there isan excessive loss of proteins, for example, after injury, post-operativetrauma, severe malnutrition, gastrointestinal tract damage and the like(Howe & Max, 1949). U.S. Pat. No. 3,764,703-A consists of a mixture ofeight essential amino acids optionally combined with L-arginine or Lhistidine for use in patients with chronic kidney disease where themixture for intravenous administration contains 2.5 to 15 grams ofnitrogen per liter of solution (Bergstrom, et al., 1973). Said mixtureis also present in tablets for oral administration. Basically these twoprior patents involve the use of a mixture of essential amino acids.Subsequently, U.S. Pat. No. 4,100,161-A “Promotion of Protein Synthesisand Suppression of Urea Formation in the Body by Keto Analogs ofEssential Amino Acids” discloses a process for preparing a compositionfor food treatment by patenting a mixture of mixed salts formed betweenalpha-keto analogs of branched-chain amino acids, specifically ketoanalogs of valine, leucine and isoleucine, these three of the essentialamino acid series, combined with basic alpha-L-amino acids of ornithine,lysine or histidine. In addition, essential amino acids, specificallyL-tyrosine, L-threonine, as well as calcium alphahydroxy-gamma-methylthiobutyrate are added to the described mixture(Walser, Promotion of Protein Synthesis and Suppression of UreaFormation in the Body by Keto Analogs of Essential Amino Acids, 1978).With regard to essential L-amino acids, the amounts in the mixture areso small that they can be ingested by selecting proteins of highbiological quality such as whey isolated protein or egg white. It isalso extremely important to mention that in its composition said patentdescribes the use of racemic mixtures (i.e., L-isomers and D-isomers) ofalpha keto analogs of branched chain amino acids, and is very well knownscientifically that the constituent amino acids of proteins of man, all19 amino acids, are of the L series, except glycine which, notcontaining a chiral carbon, lacks isomers thereof, so that, strictlyspeaking, only 25% of said composition, L-keto analogs of amino acidsvaline, leucine and isoleucine are extremely useful and effectivelycapture the serum ammonium to be transformed into the correspondingamino acids valine, leucine and isoleucine. Walser's U.S. Pat. No.4,100,293-A consists of the use of alpha keto analogs of valine,leucine, isoleucine, phenylalanine, methionine and L histidine. Inaddition, the mixture may contain L-arginine, L-lysine, L-threonine andL-tryptophan for the treatment of hepatic diseases with hyperammonemiaor portosystemic encephalopathy, as well as for the treatment ofchildren with congenital hyperammonemia due to alterations in theenzymes of the urea cycle or Krebs-Henseleit. Walser's U.S. Pat. No.4,228,099-A describes the use of ornithine and arginine salts, combinedwith salts of keto analogs of branched-chain amino acids, valine,leucine and isoleucine, in the treatment of patients with liver diseaseswho are suffering from hyperammonemia and portosystemic encephalopathy.The use of these compounds in the treatment of patients with renalinsufficiency is also useful. Walser's U.S. Pat. No. 4,296,127-Aconsists of mixed salts of semi-essential and essential amino acids.Semi-essential amino acids are selected from ornithine, arginine,cysteine, cystine and tyrosine, from the L series, for use in patientswith liver or kidney disease, as well as in patients with nitrogen lossand protein malnutrition. The essential amino acids are selected fromvaline, leucine, isoleucine, methionine, lysine, phenylalanine,threonine, tryptophan and histidinal, all of the L series. Walser's U.S.Pat. No. 4,320,146-A consists of a mixture of ornithine and argininesalts, with alpha keto analogs of valine, leucine and isoleucine. Thecompounds are useful, whether alone, singly or in combination, for thetreatment of patients with liver disease or kidney disease. In addition,Walser describes in his Patent CA-2317038-C that the administration of adietary supplement tablet containing a mixture of L-histidine,L-isoleucine, L-leucine, L-lysine, L-methionine, L-phenylalanine,L-threonine, L-tryptophan, L-tyrosine and L-valine, can prevent and/orcorrect hypoalbuminemia in patients on dialysis. U.S. Pat. No.4,957,938-A of Anderson et al. describes an improved nutritionalformulation for the treatment of patients with renal disease consistingof a mixture of 4 salts of ketoacids of amino acids and L amino acids inwhich the palatability of the mixture, its thermal stability and shelflife is substantially improved. U.S. Pat. No. 4,752,619-A of Walser etal. also consists of a mixture of salts of L amino acids and ofketo-analogues of amino acids. Calton's Patent US-20070141121-A1describes the use of the soyasaponin fraction alone or in combinationwith essential amino acids and/or the combination of keto analogs ofsaid essential amino acids. The previous treatment combined with alow-protein diet of the order of 0.6 to 0.8 grams per kilo of weight perday is suggested for the treatment of renal disease secondary topolycystic kidneys.

On the other hand, Patent CA-2331854-C of Lowry et al. describes aliquid nutritional product for oral intake or by feeding tube to improveglomerular function in people with renal failure, which as a mainconstituent, in addition to proteins, carbohydrates, fats, vitamins andminerals, contains L-arginine, and in which, to improve its palatabilityand to adjust the pH of the mixture in a range between 6 and 8, lacticacid, adipic acid or malic acid. In another modality of the nutritionalproduct of said patent, the mixture of L-arginine, proteins,carbohydrates, fats, vitamins and minerals includes citric acid incombination with citrates, these being one or more of sodium, potassiumand calcium. Although this patent states that L-arginine is essentialfor improving glomerular function, it is also true that 1) L-arginine isa non-essential amino acid that the organism autogenerates in the ureacycle or Krebs-Henseleit, where it releases a urea molecule andregenerates ornithine, 2) L-arginine is found in the average proteins ofour diet by 4.7% (see Table 1), with an atomic mass of 168 and providing2.632 grams of nitrogen out of the 18.8 grams of nitrogen contained inone mole of average protein; this is in natural conditions, but if thesestandard proteins are supplemented with a high content of L-arginine,said amino acid carrying 4 nitrogens per molecule, will contribute toincrease the metabolic pool of urea, already elevated and unable to beeliminated in a patient with renal failure. Nath's U.S. Pat. No.5,210,098-A describes the use of pyruvate or its salts intravenously forthe prevention or treatment of acute renal failure in patients at riskof having or having had such condition. Patent CN-1285340-C describesthe preparation and application of amino acid salts with sulfatedpolysaccharides in patients with chronic nephritis and renal failure. Onthe other hand, U.S. Pat. No. 4,677,121-A of Walser et al. proposes thedaily administration of alpha ketoisocaproic acid (ketoleucine) doses oran appropriate salt of such acid for the reduction or inhibition ofmuscle protein degradation in mammals, particularly humans, conditionsthat usually occur after the recovery of surgeries or diseases involvingmuscle wasting. Thomas Knerr's U.S. Pat. No. 5,945,129-A describes aprocess for the production of sterile solutions to be used as dialysissolutions, such as peritoneal dialysis or as an infusion solutioncontaining bicarbonate ions. It describes the steps in the process whereesters of carboxylic acids (molecular bonding of an acid with analcohol) are mixed with bicarbonate salts in aqueous solution and in thepresence of sterilization heat. The alcohols may be monovalent orpolyvalent and more specifically: ethanol, propranol, isopropanol,glycerol or lactone. In addition, the esters of carboxylic acids areselected from the group consisting of: glucono-o-lactone,diethylsuccinate, diethyltartrate, diethylcitrate, ettilactate anddiethylcarbonate. Shin-Jen Shiao's Patent CN-101076325A describes theuse of a pharmaceutical composition for reducing serum pH where such acomposition contains edible carboxylic acids in a proportion of 0.05 to99.9 percent of weight. Such acids to which the patent refers are:fumaric, succinic, alpha hydroxyl acids, malic, tartaric, citric, lacticacid, and their corresponding sodium and potassium salts. Additionally,such composition contains caffeine in a proportion of 0.1 to 6 percentof the weight, 0 to 80 percent of the weight of at least one herbaceousand 0 to 96 percent of the total weight of such carrier composition.This pharmaceutical composition is used to prevent, treat or improve thefollowing conditions or entities: allergic diseases, pain, infection,cold, thrombus or clotting during transfusion or dialysis, inflammation,cancer, viral infection, poisoning, memory impairment, caffeineaddiction and side effects of the cancer drug paclitaxel. In addition,carboxylic acids can be used in a proportion of 0.05 to 5 percent ofweight in combination with animal feed, this being in the proportion of85 to 99.9 percent of the dry weight. Jin Kyu Park's PatentWO-2007094600-A1 describes a composition for improving memory andlearning functions. Such composition contains one or more carboxylicacids selected from the group of: succinic acid, succinic acid salt,fumaric acid, fumaric acid salt, an emulsifier and prune concentrate(plum or maesil) or alcohol extract from maesil.

So far we have seen that patents: Howe's U.S. Pat. No. 2,457,820-A andU.S. Pat. No. 3,764,703-A describe the use of essential amino acidmixtures either orally or intravenously. U.S. Pat. No. 4,100,161-A, U.S.Pat. No. 4,100,293-A, U.S. Pat. No. 4,228,099-A, U.S. Pat. No.4,296,127-A, U.S. Pat. No. 4,320,146-A, U.S. Pat. No. 4,957,938-A,CA-2317038-C y la U.S. Pat. No. 4,752,619-A, consist of mixed orindividual salts of alpha keto analogs of branched chain amino acids,namely valine, leucine and isoleucine, in combinations with L aminoacids. On the other hand, Patent US-20070141121-A1 combines the alphaketo analogues of amino acids with the soyasaponin fraction. PatentCA-2331854-C describes the use of a nutritional product based onproteins, lipids and carbohydrates supplemented with L-arginine to beused orally or by feeding tube. Another patent, U.S. Pat. No.5,210,098-A, consists in using pyruvic acid or its salts for thetreatment of acute renal failure. Chinese Patent CN-1285340-C describesthe use of salts of sulfated polysaccharides with certain L-amino acidsas treatment for patients with chronic renal failure. European PatentEP-0624374-B1 describes the use of sulodexide and medicines containingit in the treatment of patients with diabetic nephropathy. U.S. Pat. No.5,945,129-A describes the use of parenteral or infusional dialyticsolutions consisting of esters of carboxylic acids and bicarbonate.Patent CN-101076325A describes the use of various carboxylic acidscombined with caffeine to treat, prevent and ameliorate variousconditions. Finally, Patent WO-2007094600-A1 includes succinic acid,fumaric acid or their salts to improve memory and learning.

So far there are records of patents for the treatment of patients withchronic kidney disease and other conditions based on 1) mixtures ofamino acids essential for the treatment of patients with chronicterminal or predialytic renal disease, 2) mixtures of alpha ketoanalogues of essential amino acids in combination with essential L-aminoacids, 3) alpha keto analogs mixture with soyasaponin fraction, 4)mixture of sulfated polysaccharides with certain L amino acids, 5) useof sulodexide in diabetic nephropathy and 6) use of pyruvic acid or itssalts for the treatment of acute renal failure.

SUMMARY

Our novel patent consists of a mixture of dicarboxylic and tricarboxylicacids for the nutritional treatment of patients with chronic renalfailure and other conditions, such as acute renal failure, acute orchronic hepatopathy with hyperammonemia, congenital diseases withenzymatic alterations of the urea cycle, pathological human conditionswith negative nitrogen balance, namely: sepsis, burns, postoperative,parenteral nutrition supplement entailing mixing of amino acids, enteralfeeding complement, sarcopenia, cancer, malnutrition, and diabetesmellitus. More specifically, said mixture consists of 1) racemic mixtureof malic acid (hydroxybutanedioic acid), 2) fumaric acid(trans-butenedioic acid), 3) succinic acid (butanedioic acid) and 4)citric acid (2-hydroxypropane-1,2,3-tricarboxylic acid). Such acids maybe used individually or in the following combinations, namely:

1.—citric acid in combination with succinic acid, fumaric acid and malicacid (a mixture of four acids)2.—succinic acid in combination with fumaric acid and malic acid(mixture of three acids)3.—succinic acid in combination with citric acid and malic acid (mixtureof three acids)4.—citric acid in combination with fumaric acid and malic acid (mixtureof three acids)5.—citric acid in combination with fumaric acid and succinic acid(mixture of three acids)6.—fumaric acid in combination with malic acid (mixture of two acids)7.—succinic acid in combination with malic acid (mixture of two acids)8.—succinic acid in combination with fumaric acid (mixture of two acids)9.—citric acid in combination with malic acid (mixture of two acids)10.—citric acid in combination with fumaric acid (mixture of two acids)11.—citric acid in combination with succinic acid (mixture of two acids)12—citric acid alone (a single acid, not mixed with succinic, fumaric ormalic acid)13.—succinic acid alone (a single acid, not mixed with citric, fumaricor malic acid)14.—fumaric acid alone (a single acid, not mixed with citric, succinic,or malic acid)15.—malic acid alone (a single acid, not mixed with citric, succinic, orfumaric acid)

Of such combinations, the number one is the most complete because itconsists of the mixture of three dicarboxylic acids, namely, succinicacid, fumaric acid, malic acid and a tricarboxylic acid, citric acid; intotal four different acids. However, said mixture of four acids isneither exclusive nor limiting, since the other combinations of threecarboxylic acids, namely, of combination 2 to combination 5, as well ascombinations of mixtures of two carboxylic acids selected from citricacid, malic acid, fumaric acid and succinic acid, namely, combinations 6to 11, are also beneficial in the nutritional treatment of chronic renalfailure in stages 3, 4 and 5 and other conditions. Finally, the use ofany of the aforementioned acids: citric acid, malic acid, fumaric acidor succinic acid alone, not in combination with each other, items 12 to15, are also beneficial in the treatment of chronic renal failure, aswell as in other pathologies referred to in the field of use of thepresent invention, such as the illustrative case of Nath's U.S. Pat. No.5,210,098-A, wherein pyruvic acid or its salts are used for thetreatment of acute renal failure.

The scientific bases of our novel invention, contrary to what has beensaid, stated and discussed in previous patent claims where, certainlyand effectively, the administration of alpha keto analogs of branchedchain amino acids, either alone or in combination with L-amino acids,promote the formation of their corresponding amino acids: valine,leucine and isoleucine, by obtaining via transamination the amino group,our bases are at the level of the citric acid cycle where the reversibletransamination of oxalacetate occurs to generate aspartate or byanaplerotic reaction of replacement, aspartate deamination, to generateoxalacetate. In addition to this reaction, another one occurring at thecitric acid cycle level involves the reversible transamination of alphaketo glutarate to generate glutamate or, inversely, glutamatedeamination to generate alpha keto glutarate.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a Citric acid cycle (Krebs cycle).

FIG. 2 is an Anaplerotic pathways for replacement of Krebs cycleintermediates.

FIG. 3 is an External replacement of intermediates of the citric acidcycle.

1.—Tricarboxylic acid cycle where it is seen that the entry to the cycleis via the acetyl coenzyme A (see FIG. 1), which, together withoxaloacetate, regenerates citric acid, the first target of ourinvention. After some intermediate steps the citrate generatesalpha-ketoglutarate, which subsequently generates succinyl coenzyme-A,which in turn generates succinate, the second target of our invention.Succinate loses two electrons by oxidation and creates fumarate, thirdobjective of our invention. In the immediate metabolic step, thefumarate is hydrated to form malate, the fourth objective of ourinvention. It should be noted that the salts, among others, citrate,succinate, fumarate and malate are mentioned in the tricarboxylic acidcycle. Our invention consists of mixtures of citric, succinic, fumaricand malic acids, which in the aqueous environment of the organismdissociate into their corresponding citrate, succinate, fumarate andmalate ions. Of special interest is that the cycle of citric acid is auniversal cycle that takes place not only in the human being, but in thethree domains of life on earth, i.e., in 1) domain eukarya whereanimalia, plantae, fungi and protista kingdoms are included, 2) domainarchaea and 3) domain bacteria. This cycle is a universal cycle andconstitutes the center or axis of the general metabolism of any cell, beit eukaryote with true nucleus, as is the case with all the cells of thehuman being, or prokaryotic cell, as is the case with bacteria that donot possess true nucleus. Said citric acid cycle is an amphibole cycleinvolving two very important general functions or pathways that areinterrelated, namely:

1.a) Function or catabolic pathway, in which nutrients such as proteinsvia amino acids, carbohydrates via glucose, triacylglycerols viaglycerol and fatty acids, end up as pyruvate before entering the cycleof tricarboxylic acid. By losing a carbon and generating CO₂, pyruvateis converted to acetyl coenzyme A and when it binds with the oxalacetateit regenerates the citrate to enter the citric acid cycle through thecatabolic pathway, generating energy through the formation of ATP andvarious electron carriers like NAD and FAD.

1.b) Function or anabolic pathway, in which certain intermediates of thecitric acid cycle are used for the biosynthesis of monomeric molecules.Thus, for glucose biosynthesis (gluconeogenesis), oxalacetate is used,and for biosynthesis of fatty acids we use acetyl coenzyme A. For thebiosynthesis of non-essential amino acids (glycine, L alanine, Lasparagine, L aspartate, L cysteine, L glutamate, L glutamine, Lproline, L serine and L tyrosine) the oxalacetate intermediate is usedas the initiator of synthesis, which will be formed through the acids ofour invention: succinic acid, fumaric acid and malic acid, which in theaqueous medium of our body form the corresponding succinate, fumarateand malate. Thus succinate, by the action of the enzyme succinatedehydrogenase, generates fumarate. In turn, fumarate, by action of theenzyme fumarase, generates L malate. Finally, L malate, by the action ofthe enzyme malate dehydrogenase, produces oxaloacetate. Another cycleintermediate is alpha-ketoglutarate which serves as the initiator toform glutamic acid by reversible transamination. Then, by additionaltransamination, form glutamine, as well as other related amino acids.Said alpha ketoglutarate is generated by metabolic reactions exerted onthe citric acid, which in the aqueous environment of the organism isdissociated in citrate, which is part of our invention. These methabolicreactions involve the action of the enzyme aconitase on the citrate togenerate cis-aconitate. In a second reaction, the same enzyme aconitaseacts on the cis-aconitate to form isocitrate. In the next metabolicstep, the enzyme isocitrate dehydrogenase acts on the isocitrate togenerate alpha ketoglutarate.

As shown in FIG. 2, these amino acid biosynthetic pathways, glucose andfatty acids, are pathways that extract intermediates from the cycle andare known as cataplerotic pathways or reactions, which hypotheticallyspeaking, when extracting intermediates from the cycle would exhaust it.This is not the case because, in return for this cataplerotic pathway,and since the citric acid cycle cannot be interrupted, there arereplacement pathways or reactions of these intermediaries known asanaplerotic pathways or reactions, of which the most important is thecatabolized by the enzyme pyruvate carboxylase that generatesoxalacetate from pyruvate (reaction 1). Another anaplerotic reaction forthe replacement of cycle intermediates involves the direct conversion ofphosphoenolpyruvate by the action of the enzyme phosphoenolpyruvatecarboxylase to oxalacetate (reaction 2). Another involves reversibletransamination from aspartate to oxalacetate (reaction 3). Furthermore,by the action of the malic enzyme or malate dehydrogenase on pyruvate,it catalyzes the reductive carboxylation thereof to generate malate(reaction 4). Finally, glutamate generates alpha ketoglutarate byreversible transamination (reaction 5). To sum up, so far 3 anapleroticreactions generate and replenish oxaloacetate, namely, anapleroticreaction from phosphoenolpyruvate to oxalacetate, anaplerotic reactionfrom pyruvate to oxalacetate and anaplerotic reaction from aspartate tooxaloacetate. A fourth anaplerotic reaction generates malate frompyruvate, and a last and fifth anaplerotic reaction generates alphaketoglutarate from glutamate.

In conclusion, the citric acid cycle is:

a) A universal metabolic cycle that takes place in all living beings andincludes the three domains: eukaria, which in turn includes animalia andthe human being—purpose of our invention—plantae, fungi, protist, andother two domains, the domain archaea and the domain bacteria.b) A metabolic cycle that is situated at the axis of the generalmetabolism.c) An amphibole cycle with two interrelated pathways, a catabolicpathway involving the use of carbon compounds to generate energy viaATP, as well as electron carriers such as NAD and FAD; and an anabolicpathway in which cycle intermediates, more specifically oxalacetate andalpha ketoglutarate, are used as initiator compounds for building othermolecules, most notably non-essential amino acids—subject andconsideration of the scientific basis of our patent.d) In turn, the anabolic pathway, which involves subtracting certainintermediates (oxalacetate, alpha-ketoglutarate and acetyl coenzyme A)to form new molecules different from the compounds of the cycle, knownas cataplerotic reactions, is compensated by reactions of replenishmentor filling of intermediates, called anaplerotic reactions.2.—Another scientific basis of our invention involves the knowledge thatin the urea cycle arginine is used to generate urea and ornithine by theaction of arginase. This cycle is energy-dependent, consuming ATP in theformation of urea.

Urea, the main product of excretion of nitrogen compounds in ureotelicanimals, as is the case of humans, is a small molecule with a molecularweight of 48, which by the action of intestinal urease is split intocarbon dioxide and ammonium.

Non-ureotelic animals, such as fish, remove their nitrogenous wasteproducts to the aquatic environment in the form of ammonium, notrequiring conversion to urea.

Animals such as the bear in the wintering period do not form urine, sothere must be alternate metabolic pathways to reuse the formed urea.

The Dalmatian dog, being ureotelic, eliminates its nitrogenous wastesvia uric acid.

Reptiles and birds eliminate their nitrogenous waste via uric acidformation.

In the insects there are Malpighian tubeles, which consist of tubularstructures in which the blind end of the tube is in contact with thehemolymph and the other end leads into the final part of the insect'sintestine.

From the anatomical point of view, in flat worms or plathelminthes thefirst structures specialized in excretion are given: protonephridia thaton the one hand connect with the coelom and on the other they open tothe outside of the animal through the nephridiopores. An even moreadvantageous structure in the evolution are the metanephridia appearingin mollusks and annelids. This consists of an open tubele in which theinner end opens into the coelom and the outer end is opened to theoutside by means of a nephridiopore.

With the above we notice a metabolic diversity regarding the eliminationof nitrogenous waste products: ammonium in fish, uric acid in reptilesand birds, and urea in ureothelial animals. There is also an anatomicaldiversity that remotely targets the relationship between the urinarysystem, the digestive system and the skin. By this we refer to theMalpighian tubules that connect to the intestine of insects, whichexplains the transfer of a certain amount of urea to the intestine,about 25% of the serum urea, as well as the elimination of approximately10% of serum urea through sweat, perhaps a reminder of the time whenlife on Earth was at the stage of mollusks and annelids.

Our invention consists or implies (see FIG. 3): first objective, thereplacement of citrate from citric acid which, in subsequent metabolicsteps, will first generate cis aconitate, then isocitrate and finallyalpha keto glutarate; second objective, replacement of succinate fromsuccinic acid, which in subsequent steps will generate fumarate, thenmalate, and then oxaloacetate; third objective of our invention,replacement of fumarate through fumaric acid which in a subsequent stepwill generate malate, and this, in turn, will generate oxaloacetate;fourth objective, replacement of malate through malic acid, which in thesubsequent step will generate oxaloacetate. Thus, in comparing the fiveanaplerotic reactions of the citric acid cycle, two of them, for ourinterest, are not considered since they involve transamination fromaspartate to oxalacetate and transamination from glutamate toalfacetoglutarate, since they lead to deamination of existing aminoacids. Then, there are three intermediate replacement routes left thatdo not involve transamination. Two of them replenish oxalacetate viapyruvate and phosphoenolpyruvate, and one of them replaces malate viapyruvate.

Our invention, unlike prior patents based on the administration ofessential amino acids orally or intravenously, or the use of alpha ketoanalogs of essential branched-chain amino acids in combination withessential amino acids, as well as unlike what happens in vivo inside thecell, and more specifically at the mitochondrial level—because thecitric acid cycle is performed at the mitochondrial level—, our firstobjective involves the replacement of citrate through citric acid, whichin subsequent reactions results in the formation of carbon dioxide andalpha keto glutarate, in molar proportions; thus, one mole of citrategenerates one mole of carbon dioxide and one mole of alpha ketoglutarate. This does not occur in nature because under biologicalconditions citrate is regenerated by the reaction of acetyl Coenzyme A,catalyzed by the enzyme citrate synthase on the oxaloacetate to generatecitrate. Second objective, replacement of succinate through succinicacid, which will give fumarate, then malate and finally oxalacetate,replacement condition of our invention that does not occur in biologicalsystems either. Third objective, consisting of the replacement offumarate through fumaric acid that will give malate and finallyoxalacetate, replacement of our invention which, like the replacement ofsuccinate, does not occur in biological systems. Fourth objective,consisting of the replacement of malate through malic acid, which in thecase of biological systems is carried out by action on the pyruvate ofthe malic enzyme to generate malate, but in the case of our invention, adirect replacement is provided without intervening or acting on anysubstrate or by the action of specific enzyme.

In addition, our invention consists in the option of adding otherdicarboxylic acids such as tartaric acid and/or cream of tartar to themixture to improve the palatability and solubility of said mixture, andadditionally phosphorus chelating agents such as calcium carbonateand/or calcium acetate and/or calcium gluconate and/or calcium lactate,which are extremely beneficial in the treatment of patients with chronicrenal failure in stages 4 and 5, because in this conditionhyperphosphataemia is extremely common, especially in patients withchronic long-term renal failure.

An additional element of the present patent is the incorporation ofsodium bicarbonate into the mixture of dicarboxylic acids (succinicacid, fumaric acid, malic acid and tricarboxylic citric acid). Sodiumbicarbonate is beneficial in patients with renal failure, as these occurwith chronic metabolic acidosis. In addition, it serves to balance thepH of the mixture or the carboxylic acids used in a unique way and as anantacid effect.

Another optional element or elements (may be present or not) additionalto the mixtures of this patent, is the addition of food additives toimprove patient adherence to medical treatment: (1) Artificialsweeteners such as aspartame, acesulfame and/or sucralose, and (2)natural sweeteners such as disaccharides: sucrose and/or lactose, ormonosaccharides: glucose and/or fructose.

In addition, optional additional nutraceutical substances (which may ormay not be present) are incorporated into the mixtures of thisinvention, such as: inulin, maguey honey, taurine, msm(methylsulfonylmethane), alpha lipoic acid and L carnitine.

As part of the oral treatment of the patient with chronic renal failure,in addition to the specific medications for each patient, supplementsconsisting of ascorbic acid, folic acid, ferrous sulfate, calcitriol andcomplex b are routinely prescribed, so that in order to reduce to themaximum and as much as possible the number and diversity of thedifferent and various medicines referred to, the latter, ascorbic acid,folic acid, ferrous sulfate, calcitriol and b complex, are optionallyincorporated into the carboxylic acid mixture, a possible conditiongiven the high solubility of these as well as their pleasantpalatability.

In order to calculate the amount of dicarboxylic acids to be used whichare sufficient to finally generate oxalacetate and alpha keto glutarate,and to capture ammonium via transamination derived from the metabolismof amino acids, and on a much smaller scale of the metabolism of thepyrimidine bases and other compounds carrying amino, amido or iminogroups, we will resort to the following data:

1.—A restricted diet of 0.6 to 0.8 grams per kilo of patient weight perday is suggested; then in a man of 70 kilos, the amount of protein to beconsumed will be 42 to 56 grams per day, ideally high quality biologicalproteins.2.—The average amino acids for a large number of proteins—the same onesto be ingested—is as follows: see Table 1—column 4. Of these twentyamino acids, 14 have a nitrogen (N), 4 of them carry 2 nitrogens, 1 ofthem 3 nitrogens and 1 of them 4 nitrogens. Their atomic weights areexpressed in column 6. Correlating the above data we have that one moleof average proteins would weigh 125.76 grams and would contain 18.802grams of nitrogen.

TABLE 1 Average composition of the amino acids constituent of theaverage proteins. N PROPOR- EMPIRICAL PRESENCE IN ATOMS PER ATOMICTIONAL N N NAME OF A.A. FORMULA PROTEINS⁰ A.A. MASS¹ MASS² ATOMS³ ATOMS⁴ALANINE O2C3H8N1  9% 1 90 8.1 0.09 1.26 ARGININE O2C6H16N4 4.7% 4 1687.896 0.188 2.632 ASPARAGINE O2C4H9N2 4.4% 2 117 5.148 0.088 1.232ASPARTIC O2C4H8N1 5.5% 1 102 5.61 0.055 0.77 ACID CYSTEINE O2C3H8S1N12.8% 1 122 3.416 0.028 0.392 GLUTAMINE O3C5H11N2 3.9% 2 147 5.733 0.0781.092 GLUTAMIC O4C5H10N1 6.2% 1 148 9.176 0.062 0.868 ACIDO GLYCINEO2C2H6N1 7.5% 1 76 5.7 0.075 1.05 HISTIDINE O2C6H12N3 2.1% 3 158 3.3180.063 0.882 ISOLEUCINE O2C6H14N1 4.6% 1 132 6.072 0.046 0.644 LEUCINEO2C6H14N1 7.5% 1 132 9.9 0.075 1.05 LYSINE O2C6H16N2  7% 2 148 10.360.14 1.96 METHIONINE O2C5H12S1N1 1.7% 1 150 2.55 0.017 0.238PHENYLALANINE O2C9H13N1 3.5% 1 167 5.845 0.035 0.49 PROLINE O2C5H10N14.6% 1 116 5.336 0.046 0.644 SERINE O3C3H8N1 7.1% 1 106 7.526 0.0710.994 THREONINE O3C4H10N1  6% 1 120 12 0.06 0.84 TRYPTOPHAN O2C11H16N21.1% 2 208 2.288 0.022 0.308 TYROSINE O3C9H14N1 3.5% 1 184 6.44 0.0350.49 VALINE O2C5H12N1 6.9% 1 118 8.142 0.069 0.966 100%  125.76 1.3418.8 ⁰Average for a large number of proteins. Individual proteins mayexhibit significant variations with respect to these values. ¹The atomicmasses of the elements constituting amino acids are: Hydrogen 1, Carbon12, Nitrogen 14, Oxygen 16 and Sulfur 32. ²The proportional mass of eachamino acid (A.A.) was obtained by multiplying the percentage of eachA.A. found in an average protein by its atomic mass. Hence, by adding upthe proportional mass of each amino acid that makes up a protein, weobtain that the weight of an average protein is 125.76 grams. ³Thenitrogen atoms of each amino acid in proportion to their appearance inproteins are equivalent to their mass proportional by the number ofatoms per amino acid among its atomic mass. The sum of the nitrogenatoms of each A.A. found in an average protein is equal to 1.34. ⁴Sinceone mole of nitrogen weighs 14 grams, it can be deduced that 1.34 molesof nitrogen equals 18.8 grams.According to a diet restricted to 0.6 grams of protein per kilo ofweight per day, a person of 70 kilos of weight would ingest 42 grams ofprotein, which would provide 6.28 grams of nitrogen (equivalent to448.54 millimoles of nitrogen).In the case of a diet of 0.8 grams of protein per kilo of weight perday, a person of 70 kilos of weight would ingest 56 grams of protein,which would provide 8.37 grams of nitrogen (equivalent to 598.05millimoles of nitrogen).Taking into account the Avogadro's number, where one mole of anysubstance is equal to 6.022×10²³ molecules per mole (gram molecule), wecan conclude that:3.—To capture 6.28 grams of nitrogen (448.54 millimoles of nitrogen, asone mole of nitrogen equals 14 grams) contained in 42 grams of protein,we need the same amount of millimoles of dicarboxylic and tricarboxylicacids; this in basal conditions, it is obvious to mention that insituations of stress, such as sepsis, surgery, burns, consumptivediseases and diabetes, the requirements would increase.Since the carboxylic acid mixture has an average mass of 140 to equalparts (see Table 2), one mole of this mixture is equal to 140 grams. Toobtain 448.54 millimoles of such acids, 62.79 grams of these are needed,and to obtain 598.05 millimoles 83.73 grams of dicarboxylic andtricarboxylic acids are needed.

TABLE 2 Average molar weight of carboxylic acids and their mixtures inequal parts. ATOMIC CARBOXYLIC ACIDS MASS Succinic Acid 118 Fumaric Acid116 Malic Acid 134 Citric Acid 192 AVERAGE WEIGHT (in equal proportions)140

Excretion of urea and other low molecular weight nitrogen compounds iscarried out through sweat in 10%, feces in 25%, as ammonium through theurine in 10% and another 10% by residual renal function. This representsabout 35% of the removal of nitrogen and nitrogen compounds alternatelyto renal excretion and 20% renally (10% in ammonium form as such, and10% as residual renal function). If one takes into account that of thedaily intake of proteins about 55% of the nitrogens contained in themare eliminated through these pathways, the need for ingestion of thecarboxylic acids can be reduced by half approximately. This wouldmaintain the daily requirement thereof in the order of 31.40 grams to41.86 grams of carboxylic acids for an intake of 42 and 56 grams ofprotein respectively.

The effects and, consequently, the benefits of this invention are:

1.—Capture of ammonium before the formation of urea at the liver level,thereby1.1—reducing the concentration of ammonium in the body and the toxiceffects thereof and1.2—reducing the concentration of urea in the organism and its toxiceffects thereof.2.—Capture of ammonium via dicarboxylic acids: succinic acid, fumaricacid and malic acid, which by enzymatic reactions thereon end up in theketoacid oxalacetate, which, by transamination, forms aspartate andother related amino acids. In turn, citric acid, after passing tocis-aconitate and isocitrate, loses a carbon generating CO₂ andalpha-ketoglutarate, which by transamination will generate glutamate andrelated amino acids.2.1—improvement of nitrogen balance,2.2—increase in the synthesis of non-essential amino acids,2.3—improvement of nutritional status and2.4—increase in serum albunim levels in the blood.3.—Improvement of palatability versus prior patents based on mixtures ofcalcium salts of alpha keto analogs of branched chain amino acids andmixture of L amino acids.4.—Improvement of patient adherence to treatment.5.—Improvement of the quality of life.6.—Decrease in treatment costs.7.—Additionally the phosphate is chelated from food by incorporatingcalcium carbonate and/or calcium acetate and/or calcium gluconate and/orcalcium lactate into the mixture. This incorporation of calcium saltsinto the mixture contains the following benefits:7.1—Contributes to the mixture pH damping,7.2—gastric protection,7.3—additional cost reduction and overall adherence to the treatment ofend-stage renal disease, due to the additional use ofphosphorus-chelating drugs, otherwise the patient should consumephosphorus-chelating drugs separately.8.—Improvement of metabolic acidosis, a very common condition ofpatients with renal failure stages 4 and 5, with the addition of sodiumbicarbonate which is added for two purposes:8.1—dampening of the dicarboxylic acids mixture,8.2—improvement of metabolic acidosis characteristic of CRF stages 4 and5, and8.3—protection against hyperkalemia and the adverse and potentiallylethal effects thereof, which is aggravated in the presence of acidosis.The treatment with dicarboxylic and tricarboxylic acids prevents,preserves and even improves renal function, avoiding renal replacementtherapy, poor quality of life of the patient and the extremely highfinancial costs borne by relatives and/or institutions of the healthsector of the States. Finally, it prevents frequent hospitalizations asa consequence of the inherent therapeutic procedures and thecomplications thereof. In other patients it delays deterioration ofrenal function and the urgent need for renal replacement therapy. Inthis group of patients, laboratory parameters and quality of life aremaintained favorably while waiting for a kidney transplant. In others,it is used as a treatment complementary to renal replacement therapy toimprove the patient's quality of life and improve laboratory parameters.The following clinical cases illustrate the benefits and achievements ofthis invention:Case 1.—Retrospective study: A 82-year-old male with a history ofDiabetes Mellitus type II of over 25 years of evolution was diagnosedwith Terminal Renal Failure Stage V in August 2010 with a serum urea of129.5, creatinine 3.3, BUN 60.51, hb 11.8, potassium 5.1, phosphorus4.5, calcium 9.4 and general urine with proteinuria of 250 mg/liter.Nephrology started protocol for initiation of peritoneal dialysis. InNovember 2010, before starting treatment with oral carboxylic acids, the24-hour urine creatinine clearance was 16.46 ml/min, with a urinaryvolume of 17.5 deciliters, serum creatinine of 3.14 and urinarycreatinine of 39.82 mg/dl. The patient refused peritoneal dialysis renalreplacement therapy and initiated treatment consisting of the currentinvention, combined with a low protein diet of the order of 0.6 to 0.8grams of protein per kilo per day. In July 2014, he broke is hip, whichresulted in a total prosthesis thereof, blood transfusion of 2 units andhis biochemical parameters were: hb 11.5, urea 141, creatinine 3.2, BUN66, serum ammonium 5 (normal 9-33). In August 2014 his 24-hour urinecreatinine clearance was 25.36 ml/min with a urinary volume of 23.7deciliters, serum creatinine of 2.41 and urinary creatinine of 33.91. InNovember 2014, the patient completed 4 years in treatment. Animprovement in creatinine clearance in the 24-hour urine of an initialpretreatment value of 16.46 ml/min is observed, which even 4 years laterremains above these values, the last clearance being 25.36 ml/min.Case 2.—Retrospective study: a 50-year-old female with a history ofsevere arterial hypertension with a previous figure of 240/140 mmHg. InSeptember 2013 she started renal replacement therapy with hemodialysis,3 sessions per week for 2 consecutive months. After 2 months ofhemodialysis, the laboratory parameters are: hb 10, serum creatinine6.7, urea 133, 24-hour urine creatinine clearance 10.84 ml/min. InNovember 2013, she started treatment with oral carboxylic acids, as wellas a low-protein diet of 0.6 to 0.8 grams/kilo/day. She did not continueattending the hemodialysis sessions, so at the end of January 2014 thecentral catheter was removed. The last assessment of the patient was inSeptember 2014. It is should be mentioned that during the last twomonths the patient had suspended treatment with carboxylic acids becausethey did not have them. Her laboratory tests in September 2014 are: hb9.6, serum creatinine 5.1, urea 200, BUN 84, potassium 5.2, phosphorus6.8, calcium 8.2, albumin 4.4. After 60 days of hemodialysis, one yearwithout dialytic treatment and 2 months of discontinuation of carboxylicacid treatment, the patient showed a decrease of 0.4 in hemoglobin,reduction in serum creatinine from 6.7 to 5.1, and a moderate increasein urea from 133 to 200.Case 3.—Retrospective Study: A 72-year-old male with a history ofsystemic arterial hypertension, diabetes mellitus of 40 years ofevolution and ESRD. In November 2012 the laboratory analysis showed: hb12.2, serum creatinine 5.3, urea 127, BUN 59. He refused renalreplacement therapy and in November 2012 he began with treatment of oralcarboxylic acids. At this time he had a serum creatinine of 6.74, urea209, BUN 97.7. In November 2013, the date of his last visit, hislaboratory tests were: serum creatinine of 3.9, urea of 58, BUN 27.Eight months later he had pneumonia and myocardial infarction,endotracheal intubation was performed and he died as a consequence ofmyocardial infarction. In a year of treatment with carboxylic acids, thepatient's nitrogen levels were improved: serum creatinine was reduced bymore than 42% and urea decreased by 72%.Case 4—Retrospective study: 35-year-old male diagnosed with end-stagerenal disease secondary to hypoplastic kidneys. In May 2014, he startedrenal replacement therapy with acute dialysis; his laboratory tests atthat date were hb of 6.9, serum creatinine 21.3, urea 216 and potassium4.4. One month later he started with intermittent peritoneal dialysisconsisting of 20 sessions each week. At the onset of IPD, his laboratorytests showed hb of 7.4, serum creatinine 17, urea 226, uric acid 10.1,urine creatinine clearance of 24 hours of 2.65 ml/minute. In July 2014,laboratory tests show: hb 8.4, serum creatinine 17.7, urea 215. OnSeptember 2 he started treatment with oral carboxylic acids, coupledwith a low protein diet. On Sep. 22, 2014, 20 days after initiating suchtreatment, he began with continuous ambulatory peritoneal dialysisconsisting of 4 sessions per day. On Oct. 20, 2014, two months afterstarting treatment with carboxylic acids and one month after startingambulatory peritoneal dialysis, he showed dramatic laboratory studies:hb 12.7, serum creatinine 12.77, and urea 86.2.

1. A method of reducing uremia and hyperphosphatemia in patients withchronic renal failure, comprising administering to a patient in needthereof a therapeutically effective amount of a composition comprisingcitric acid, succinic acid, fumaric acid, and malic acid, in combinationwith sodium bicarbonate, calcium carbonate and calcium lactate.
 2. Themethod according to claim 1, wherein the therapeutically effectiveamount of the composition administers to said patient is 12 to 1800millimoles (2.304 grams to 345.6 grams) of citric acid per day.
 3. Themethod according to claim 1, wherein the therapeutically effectiveamount of the composition administers to said patient is 10 to 1800millimoles (1.18 grams to 212.4 grams) of succinic acid per day.
 4. Themethod according to claim 1, wherein the therapeutically effectiveamount of the composition administers to said patient is 10 to 1800millimoles (1.16 grams to 208.8 grams) of fumaric acid per day.
 5. Themethod according to claim 1, wherein the therapeutically effectiveamount of the composition administers to said patient is 10 to 1800millimoles (1.34 grams to 241 grams) of malic acid per day.
 6. Themethod according to claim 1, wherein the composition is formulated: (i)as a powder to be reconstituted in drinking water or fruit juice; (ii)as effervescent tablets; or (iii) to be premixed or pre-constituted infruit juices or ingestible drinks.
 7. The method according to claim 1,wherein the composition further comprises vitamin C, folic acid, ferroussulfate, B complex and/or calcitriol.
 8. The method according to claim1, wherein the composition further comprises artificial sweeteners ofacesulfame, aspartame and/or sucralose.
 9. The method according to claim1, wherein the composition further comprises monosaccharides of fructoseand/or glucose; disaccharides of sucrose and/or lactose; and/oroligosaccharides of inulin and/or maguey honey.
 10. The method accordingto claim 1, wherein the composition further comprises taurine and/or Lcarnitine.